The effects of Share 35 on the cost of liver transplantation.

On June 18, 2013, the United Network for Organ Sharing (UNOS) instituted a change in the liver transplant allocation policy known as "Share 35." The goal was to decrease waitlist mortality by increasing regional sharing of livers for patients with a model for end-stage liver disease (MELD) score of 35 or above. Several studies have shown Share 35 successful in reducing waitlist mortality, particularly in patients with high MELD. However, the MELD score at transplant has increased, resulting in sicker patients, more complications, and longer hospital stays. Our study aimed to explore factors, along with Share 35, that may affect the cost of liver transplantation. Our results show Share 35 has come with significantly increased cost to transplant centers across the nation, particularly in regions 2, 5, 10, and 11. Region 5 was the only region with a median MELD above 35 at transplant, and cost was significantly higher than other regions. Several other recipient factors had changes with Share 35 that may significantly affect the cost of liver transplant. While access to transplantation for the sickest patients has improved, it has come at a cost and regional disparities remain. Financial implications with proposed allocation system changes must be considered.

ECD kidney transplantation outcomes are improved when matching donors to recipients using a novel creatinine clearance match ratio (CCMR).

Improved outcomes have been associated with various methods of size matching between expanded criteria (ECD) donors and recipients. A novel method for improved functional based matching was developed utilizing manipulation of Cockcroft-Gault estimated creatinine clearances for donor and recipient. We hypothesized that optimal clearance-based matches would have superior outcomes for both immediate graft function and long-term graft survival. For the analysis, recipients of ECD kidneys in the Scientific Registry of Transplant Recipients (SRTR) transplanted between October 1, 1987 and August 31, 2011 were included. Univariate and multivariate analyses predicted the hazard ratio of graft failure and the odds ratio of requiring dialysis within the first week. A total of 25,640 ECD kidney transplants were analyzed. On multivariate analysis, higher creatinine clearance match ratio (CCMR) was associated with increased graft failure and odds of requiring dialysis within the first week (comparing highest ratio quintile versus lowest ratio quintile: HR 1.43, p < 0.001; OR 2.08, p < 0.001). This study suggests that ECD kidneys have improved outcomes when the recipient/donor CCMR is optimized.

D-MELD risk capping improves post-transplant and overall mortality under markov microsimulation.

AIM: To hypothesize that the product of calculated Model for End-Stage Liver Disease score excluding exception points and donor age (D-MELD) risk capping ± Rule 14 could improve post liver transplant and overall survival after listing. METHODS: Probabilities derived from the United Network for Organ Sharing database between 2002 and 2004 were used to simulate potential outcomes for all patients listed for transplantation. The Markov simulation was then modified by screening matches using a 1200 or 1600 D-MELD risk cap ± allowing transplants for Model for End-Stage Liver Disease (MELD) ≤ 14 (Rule 14). The differential impact of the rule changes was assessed. RESULTS: The Markov simulation accurately reproduced overall and post transplant survival. A 1200 D-MELD risk cap improved post-transplant survival. Both the 1200 and 1600 risk caps improved overall survival for waitlisted patients. The addition of Rule 14 further improved post transplant and overall survival by redistribution of donor livers to recipients in higher MELD subgroups. The mechanism for improved overall and post-transplant survival after listing was due to shifting a larger percentage of transplants to the moderate MELD score subgroup (MELD 15-29) while also ensuring that high MELD recipients have livers of high quality to achieve excellent post transplant survival. CONCLUSION: A 1200 D-MELD risk cap + Rule 14 provided the greatest overall benefit primarily by focusing liver transplantation towards the moderate MELD recipient.

A randomized clinical trial testing the anti-inflammatory effects of preemptive inhaled nitric oxide in human liver transplantation.

Decreases in endothelial nitric oxide synthase derived nitric oxide (NO) production during liver transplantation promotes injury. We hypothesized that preemptive inhaled NO (iNO) would improve allograft function (primary) and reduce complications post-transplantation (secondary). Patients at two university centers (Center A and B) were randomized to receive placebo (n = 20/center) or iNO (80 ppm, n = 20/center) during the operative phase of liver transplantation. Data were analyzed at set intervals for up to 9-months post-transplantation and compared between groups. Patient characteristics and outcomes were examined with the Mann-Whitney U test, Student t-test, logistic regression, repeated measures ANOVA, and Cox proportional hazards models. Combined and site stratified analyses were performed. MELD scores were significantly higher at Center B (22.5 vs. 19.5, p<0.0001), surgical times were greater at Center B (7.7 vs. 4.5 hrs, p<0.001) and warm ischemia times were greater at Center B (95.4 vs. 69.7 min, p<0.0001). No adverse metabolic or hematologic effects from iNO occurred. iNO enhanced allograft function indexed by liver function tests (Center B, p<0.05; and p<0.03 for ALT with center data combined) and reduced complications at 9-months (Center A and B, p = 0.0062, OR = 0.15, 95% CI (0.04, 0.59)). ICU (p = 0.47) and hospital length of stay (p = 0.49) were not decreased. iNO increased concentrations of nitrate (p<0.001), nitrite (p<0.001) and nitrosylhemoglobin (p<0.001), with nitrite being postulated as a protective mechanism. Mean costs of iNO were $1,020 per transplant. iNO was safe and improved allograft function at one center and trended toward improving allograft function at the other. ClinicalTrials.gov with registry number 00582010 and the following URL:http://clinicaltrials.gov/show/NCT00582010.

Extracorporeal delivery of rAAV with metabolic exchange and oxygenation.

Over the past decade much progress has been made towards the treatment of disease with recombinant adeno-associated viral vectors, ranging from cancer to muscular dystrophies, and autoimmune diseases to cystic fibrosis. Given inherent challenges of vector delivery we developed a system incorporating commercially available dialysis equipment. This concept was evaluated in vitro utilizing rAAV expressing the reporter gene human placental alkaline phosphatase. A number of pre-circulating conditions were assessed. Vector recovery was evaluated by quantitative vector genome analysis and cellular transduction assays. A dialysis circulation time course was established, and results were recorded across varied conditions ranging from approximately 2 to 90% retention of viable vector. This approach is unique in that it focuses on efficient localized, isolated and continual delivery of vector to target tissues, provides for the preservation of tissue integrity with dialysis for metabolic exchange and allows for the transfer of oxygen through a secondary membrane post-dialysis.

Center competition and outcomes following liver transplantation.

In the United States, livers for transplantation are distributed within donation service areas (DSAs). In DSAs with multiple transplant centers, competition among centers for organs and recipients may affect recipient selection and outcomes in comparison with DSAs with only 1 center. The objective of this study was to determine whether competition within a DSA is associated with posttransplant outcomes and variations in patients wait-listed within the DSA. United Network for Organ Sharing data for 38,385 adult cadaveric liver transplant recipients undergoing transplantation between January 1, 2003 and December 31, 2009 were analyzed to assess differences in liver recipients and donors and in posttransplant survival by competition among centers. The main outcome measures that were studied were patient characteristics, actual and risk-adjusted graft and patient survival rates after transplantation, organ quality as quantified by the donor risk index (DRI), wait-listed patients per million population by DSA, and competition as quantified by the Hirschman-Herfindahl index (HHI). Centers were stratified by HHI levels as no competition or as low, medium (or mid), or high competition. In comparison with DSAs without competition, the low-, mid-, and high-competition DSAs (1) performed transplantation for patients with a higher risk of graft failure [hazard ratio (HR) = 1.24, HR = 1.26, and HR = 1.34 (P < 0.001 for each)] and a higher risk of death [HR = 1.21, HR = 1.23, and HR = 1.34 (P < 0.001 for each)] and for a higher proportion of sicker patients as quantified by the Model for End-Stage Liver Disease (MELD) score [10.0% versus 14.8%, 20.1%, and 28.2% with a match MELD score of 31-40 (P < 0.001 for each comparison)], (2) were more likely to use organs in the highest risk quartile as quantified by the DRI [18.3% versus 27.6%, 20.4%, and 31.7% (P ≤ 0.001 for each)], and (3) listed more patients per million population [18 (median) versus 34 (P = not significant), 37 (P = 0.005), and 45 (P = 0.0075)]. Significant variability in patient selection for transplantation is associated with market variables characterizing competition among centers. These findings suggest both positive and negative effects of competition among health care providers.

Use of an automated clinical management system improves outpatient immunosuppressive care following liver transplantation.

OBJECTIVE: Immunosuppressive therapy following transplantation, if not managed well, can lead to increased drug toxicity or rejection episodes. We investigated whether use of an automated clinical management system in our liver transplant program would improve clinical outcomes in managing transplant recipients' immunosuppressive medications. DESIGN: We performed a retrospective cohort study of two patient groups receiving liver transplants at our institution. One group of 301 patients transplanted from January 1, 2004 to November 30, 2006 received outpatient immunosuppressive management using a paper charting system. After instituting an automated clinical management system, the following group of 127 patients transplanted from December 12, 2006 to April 1, 2008 received their outpatient immunosuppressive management with that system. Only patients who received tacrolimus therapy, with or without mycophenolate mofetil or prednisone, were studied. MEASUREMENTS: Our endpoints included percentage of patients having rejection and/or tacrolimus toxicity episodes. Various recipient, intraoperative, donor, and postoperative variables, including managing the immunosuppressive therapy with a paper charting system or an automated management system, were studied to determine which factors were associated with our endpoints. RESULTS: Multivariable logistic regression analysis showed the automated system was significantly associated with fewer rejection episodes and fewer tacrolimus toxicity events. Formal cost-effectiveness analysis of the nurses' salaries for 1 year showed the automated system cost US$197 per patient and the paper system cost US$1703 per patient. The automated system improved quality of life years. CONCLUSION: Use of an automated clinical management system for outpatient immunosuppressive management for liver transplant patients has resulted in a decrease in both tacrolimus toxicity and rejection episodes and is cost-effective.

Intraoperative portal vein blood flow predicts allograft and patient survival following liver transplantation.

BACKGROUND: We hypothesized that operative variables might predict survival following liver transplantation. METHODS: We examined perioperative variables from 469 liver transplants carried out at the University of Washington during 2003-2006. Logistic regression determined the variables' contributions to survival at 30, 90 and 365 days. RESULTS: Portal vein blood flow (>1 l/min) was significant to patient survival at 30, 90 and 365 days. Complete reperfusion was only a significant predictor of survival at 30 days. This provided model receiver operating characteristic (ROC) area under the curve (AUC) statistics of 0.93 and 0.87 for 30 and 90 days, respectively. At 365 days, hepatic artery blood flow (>250 ml/min) combined with portal vein blood flow was significantly predictive of survival, with an AUC of 0.74. A subset analysis of 110 transplants demonstrated improved 1-year survival with more aggressive vascular revisions. DISCUSSION: Portal vein blood flow is a significant predictor of survival after liver transplantation. Initially, the liver's survival is based on portal vein blood flow; however, subsequent biliary problems and patient demise result from both poor portal vein and inadequate hepatic artery blood flow.

The biopsied donor liver: incorporating macrosteatosis into high-risk donor assessment.

To expand the donor liver pool, ways are sought to better define the limits of marginally transplantable organs. The Donor Risk Index (DRI) lists 7 donor characteristics, together with cold ischemia time and location of the donor, as risk factors for graft failure. We hypothesized that donor hepatic steatosis is an additional independent risk factor. We analyzed the Scientific Registry of Transplant Recipients for all adult liver transplants performed from October 1, 2003, through February 6, 2008, with grafts from deceased donors to identify donor characteristics and procurement logistics parameters predictive of decreased graft survival. A proportional hazard model of donor variables, including percent steatosis from higher-risk donors, was created with graft survival as the primary outcome. Of 21,777 transplants, 5051 donors had percent macrovesicular steatosis recorded on donor liver biopsy. Compared to the 16,726 donors with no recorded liver biopsy, the donors with biopsied livers had a higher DRI, were older and more obese, and a higher percentage died from anoxia or stroke than from head trauma. The donors whose livers were biopsied became our study group. Factors most strongly associated with graft failure at 1 year after transplantation with livers from this high-risk donor group were donor age, donor liver macrovesicular steatosis, cold ischemia time, and donation after cardiac death status. In conclusion, in a high-risk donor group, macrovesicular steatosis is an independent risk factor for graft survival, along with other factors of the DRI including donor age, donor race, donation after cardiac death status, and cold ischemia time.

Donor-recipient size matching influences early but not late graft function after pediatric en-bloc kidney transplantation.

BACKGROUND: Pediatric en-bloc kidney transplantation into adult recipients is an accepted technique to expand the donor pool. Concerns about adequate "nephron dosing" have traditionally favored placing these kidneys into smaller recipients. METHODS: We reviewed 20 pediatric en-bloc transplants performed at our institution between 2002 and 2008. We examined the impact of donor age, donor weight, recipient sex, combined kidney length, recipient weight, recipient-to-donor weight ratio, and recipient weight gain on serum creatinine over time using regression analysis. RESULTS: Patient survival was 100%. Two grafts were lost early from vascular thrombosis. Of the remaining 18 recipients, all had immediate and excellent long-term function with average creatinine of 0.91+/-0.38 mg/dL at a mean follow-up of 1257+/-656 days. For 17 patients with 1 year follow-up, recipient weight, recipient-to-donor weight ratio, and recipient male sex negatively influenced renal function at 1 month. However, this relationship was lost by 1 year with increasing function in the smallest donors and largest size mismatches. Between 1 month and 1 year posttransplant, estimated creatinine clearance improved from 59+/-13 mL/min at 1 month posttransplant to 88+/-41 mL/min (P<0.015). Weight gain after transplant was associated with improved creatinine clearance, suggesting continued adaptation over time. CONCLUSIONS: We conclude that donor or recipient size matching up to a recipient-to-donor weight ratio of 7.5 does not significantly impact later renal function after pediatric en-bloc kidney transplantation into adults.

The impact of consecutive operations on survival after liver transplantation.

The impact of surgeon fatigue on patient outcomes has not been previously studied. In order to assess the relationship of surgeon workload to patient outcome, we analyzed the impact of the interval between liver transplants and the cumulative number of liver transplants in a week on patient outcome. The outcomes of 390 liver transplants performed between 2003 and 2006 at the University of Washington Medical Center were analyzed. Overall 1-year patient/graft survival was significantly higher if the primary surgeon had >2 days between transplants (< or =2 days between transplants, 82.8%/81.5%, versus >2 days between transplants, 92.5%/91.2%, P < 0.003/0.004). Patient survival was also improved if a surgeon performed < or =3 liver transplants in 1 week versus > or =4 (90.4% versus 80.9%, P < 0.026). No other analyzed complication reached significance. Surgeon fatigue from successive transplants may potentially affect liver transplant survival. Call schedules should recognize the potential impact of workload on liver transplant outcome. Liver Transpl 15:907-914, 2009. (c) 2009 AASLD.

Intraoperative dialysis during liver transplantation with citrate dialysate.

Liver transplantation for acutely ill patients with fulminant liver failure carries high intraoperative and immediate postoperative risks. These are increased with the presence of concomitant acute kidney injury (AKI) and intraoperative dialysis is sometimes required to allow the transplant to proceed. The derangements in the procoagulant and anticoagulant pathways during fulminant liver failure can lead to difficulties with anticoagulation during dialysis, especially when continued in the operating room. Systemic anticoagulation is unsafe and regional citrate anticoagulation in the absence of a functional liver carries the risk of citrate toxicity. Citrate dialysate, a new dialysate with citric acid can be used for anticoagulation in patients who cannot tolerate heparin or regional citrate. We report a case of a 40-year-old female with acetaminophen-induced fulminant liver failure with associated AKI who underwent intraoperative dialytic support during liver transplantation anticoagulated with citrate dialysate during the entire procedure. The patient tolerated the procedure well without any signs of citrate toxicity and maintained adequate anticoagulation for patency of the dialysis circuit. Citrate dialysate is a safe alternative for intradialytic support of liver transplantation in fulminant liver failure.

Evaluation of vascular delivery methodologies to enhance rAAV6-mediated gene transfer to canine striated musculature.

A growing body of research supports the development of recombinant adeno-associated viral (rAAV) vectors for delivery of gene expression cassettes to striated musculature as a method of treating severe neuromuscular conditions. However, it is unclear whether delivery protocols that achieve extensive gene transfer in mice can be adapted to produce similarly extensive gene transfer in larger mammals and ultimately patients. Consequently, we sought to investigate methodological modifications that would facilitate rAAV-mediated gene transfer to the striated musculature of canines. A simple procedure incorporating acute (i) occlusion of limb blood flow, (ii) exsanguination via compression bandage, and (iii) vector "dwell" time of <20 minutes, markedly enhanced the transduction of limb muscles, compared with a simple bolus limb infusion of vector. A complementary method whereby vector was infused into the jugular vein led to efficient transduction of cardiomyocytes and to a lesser degree the diaphragm. Together these methods can be used to achieve transgene expression in heart, diaphragm, and limb muscles of juvenile dogs using rAAV6 vectors. These results establish that rAAV-mediated gene delivery is a viable approach to achieving systemic transduction of striated musculature in mammals approaching the dimensions of newborn humans.

Should liver transplantation in patients with model for end-stage liver disease scores

Studies have shown that liver transplantation offers no survival benefits to patients with Model for End-Stage Liver Disease (MELD) scores or=18 years) listed for or undergoing primary liver transplantation in the United States for chronic liver disease from 1/1/2003 through 12/31/2007 with follow-up until 2/1/2008. The "Rule 14" policy gave a 3% improvement in overall patient survival over the present system at 1, 2, 3, and 4 years and predicted a 13% decrease in overall waitlist time for patients with MELD scores of 15 to 40. Patients with the greatest benefit from a "Rule 14" policy were those with MELD scores of 6 to 10, for whom a 17% survival advantage was predicted from waiting on the list versus undergoing transplantation. Our analysis supports changing the national liver allocation policy to not allow liver transplantation for patients with MELD

Identifying risk for recurrent hepatocellular carcinoma after liver transplantation: implications for surveillance studies and new adjuvant therapies.

The recurrence of hepatocellular carcinoma (HCC) is a major cause of mortality for patients transplanted with HCC. There currently exists no standard method for identifying those patients with a high risk for recurrence. Identification of factors leading to recurrence is necessary to develop an efficient surveillance protocol and address new potential adjuvant therapies. We conducted a retrospective review of 834 consecutive liver transplants from 1/1/1996 to 12/31/2005 (mean follow-up 1303 +/- 1069 days) at one institution and 352 consecutive transplants from 1/2/2002 to 12/31/2005 (mean follow-up 836 +/- 402 days) at a second institution. The test cohort comprised patients identified with HCC in their explanted livers from 1/1/2001 to 12/31/2005 at the first institution. Explant pathology and donor and recipient characteristics were reviewed to determine factors associated with HCC recurrence. These predictors were validated in the remaining liver transplant recipients. The test cohort had 116 patients with findings of HCC in their explanted livers. Twelve patients developed recurrent HCC. Stepwise logistic regression identified 4 independent significant explant factors predictive of recurrence. Size of one tumor (>4.5 cm), macroinvasion, and bilobar tumor were positive predictors of recurrence, whereas the presence of only well-differentiated HCC was a negative predictor. Designating each significant factor with points in relation to its odds ratio, a Predicting Cancer Recurrence Score (PCRS) with results ranging from -3 to 6 was developed that accurately determined risk of recurrence. These findings were then applied to the two validation cohorts, which confirmed the high predictive value of this model. In conclusion, patients transplanted for HCC with a PCRS of < or =0 have a low risk of recurrence. Patients with a PCRS of 1 or 2 have a moderate risk of recurrence, and those with a PCRS of > or =3 have a high risk for recurrence.

Ischemic cholangiopathy following liver transplantation from donation after cardiac death donors.

The use of donation after cardiac death (DCD) donor hepatic allografts is becoming more widespread; however, there have been published reports of increased graft failure from specific complications associated with this type of allograft. The complication of ischemic cholangiopathy (IC) has been reported to occur more frequently after the use of DCD hepatic allografts. We report the results of 52 liver transplants from DCD donors and the factors that influenced the development of IC. We conducted a retrospective review of all DCD and donation after brain death (DBD) donor liver recipients from September 2003 through December 2006 at a single institution. Survival and complication rates were compared between the 2 groups. The Cox proportional hazards model was then used to identify recipient and donor factors that predict the development of IC in the DCD group. There was no difference in 1-year patient or graft survival rates between the 2 groups. There was no incidence of primary nonfunction from the DCD allografts. Hepatic artery complications and anastomotic bile duct complications were comparable in the 2 groups. There was, however, an increased risk for the development of IC in the DCD group (13.7% versus 1%, P = 0.001). Donor weight >100 kg and total ischemia times > or =9 hours, in donors older than 50 years of age, predicted the development of IC in the DCD group. In conclusion, there is a higher incidence of IC in recipients receiving DCD donor livers; however, patient and graft outcomes with DCD donors remain comparable to those with DBD donors. Careful donor selection may improve utilization of these grafts.

Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis.

BACKGROUND: Antiviral prophylaxis has been shown to decrease the incidence of cytomegalovirus (CMV) disease in organ transplant recipients, but whether CMV disease that occurs despite prophylaxis is associated with mortality remains unknown. METHODS: The clinical features and risk factors for CMV disease in a cohort of liver transplant recipients who received antiviral prophylaxis were assessed retrospectively. Cox proportional hazard regression was used to assess the relationship of CMV to mortality during the first posttransplant year. RESULTS: CMV disease developed in 37 of 437 (8.5%) recipients at a median of 4.5 (range, 2.5 to 12) months posttransplant and was associated only with donor-seropositive/recipient-seronegative serostatus in multivariate analysis (P<0.0001). Mortality at 1 year was 12% (51 of 437) and was infection-associated in 49% of cases. In multivariate analysis, CMV disease was independently associated with overall mortality at 1 year (HR, 5.1, P=0.002) and even more strongly with infection-associated mortality (HR 11, P=0.002). There was no association of CMV with noninfection-associated mortality (P>0.05). CONCLUSIONS: Late CMV disease is an important clinical problem in liver transplant recipients who receive antiviral prophylaxis, and is strongly and independently associated with mortality. Strategies to prevent late CMV disease are warranted.

Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis.

BACKGROUND: The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined. METHODS: The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models. RESULTS: CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04-0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8-54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R-) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R- status was the only variable significantly associated with CMV disease in multivariate analysis. CONCLUSIONS: Late CMV disease develops in a substantial proportion of D+R- recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R- patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.